Compounds and methods to treat cardiac failure and other disorders

ABSTRACT

The invention is directed to compounds of the formula  
                 
 
     and the pharmaceutically acceptable salts thereof  
     wherein Ar 1  is indole, benzimidazole, or benzotriazole, optionally substituted with lower alkyl (1-4C), halo, or lower alkoxy (1-4C);  
     X 1  is CO or an isostere thereof;  
     Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;  
     n is 0 or 1;  
     Z is CH or N;  
     X 2  is CH, CH 2  or an isostere thereof; and  
     Ar 2  consists of one or two phenyl moieties directly coupled to X 2  and optionally substituted by halo, nitro, alkyl (1-6C), CN or CF 3 , or by RCO, COOR, CONR 2 , NR 2 , OR or SR, wherein R is H or alkyl (1-6C) or by phenyl, itself optionally substituted by the foregoing substituents;  
     with the proviso that if Z is N, X 1  is CO, and Ar 1  is indole, Ar 1  must be coupled to X 1  through the  2, 5 -,  6 - or  7 -position.  
     These compounds are useful in the treatment of conditions associated with inflammation. In addition, the above compounds and other compounds described herein are useful in treating conditions associated with cardiac failure.

TECHNICAL FIELD

[0001] The invention is directed to compounds that are useful intreating inflammation and that contain piperazine or piperidine moietiescoupled to indole, benzimidazole or benzotriazole. More particularly,the invention concerns novel compounds of this type as well as methodsto treat heart and kidney conditions using these and other compounds.

BACKGROUND ART

[0002] A large number of chronic and acute conditions have beenrecognized to be associated with perturbation of the inflammatoryresponse. A large number of cytokines participate in this response,including IL-1, IL-6, IL-8 and TNF. It appears that the activity ofthese cytokines in the regulation of inflammation rely at least in parton the activation of an enzyme on the cell signaling pathway, a memberof the MAP kinase family generally known as p38 and alternatively knownas CSBP and RK. This kinase is activated by dual phosphorylation afterstimulation by physiochemical stress, treatment with lipopolysaccharidesor with proinflammatory cytokines such as IL-1 and TNF.

[0003] Therefore, inhibitors of the kinase activity of p38 are usefulantiinflammatory agents. PCT applications WO98/06715, WO98/07425, and WO96/40143, all of which are incorporated herein by reference, describethe relationship of p38 kinase inhibitors with various disease states.As mentioned in these applications, inhibitors of p38 kinase are usefulin treating a variety of diseases associated with chronic inflammation.These applications list rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, sepsis,septic shock, endotoxic shock, Gram-negative sepsis, toxic shocksyndrome, asthma, adult respiratory distress syndrome, stroke,reperfusion injury, CNS injuries such as neural trauma and ischemia,psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcosis, bone resorption diseases such asosteoporosis, graft-versus-host reaction, Crohn's Disease, ulcerativecolitis including inflammatory bowel disease (IBD) and pyresis.

[0004] The above-referenced PCT applications disclose compounds whichare p38 kinase inhibitors said to be useful in treating these diseasestates. These compounds are either imidazoles or are indoles substitutedat the 3- or 4-position with a piperazine ring linked through acarboxamide linkage. Additional compounds which are conjugates ofpiperazines with indoles are described as insecticides in WO97/26252,also incorporated herein by reference.

DISCLOSURE OF THE INVENTION

[0005] The invention is directed to compounds useful in treatinginflammation generally, including specific conditions such as thosedescribed in the Background section above. Certain novel compounds havebeen found to inhibit p38 kinase and are thus useful in treatingdiseases mediated by this enzyme. The compounds of the invention are ofthe formula

[0006] and the pharmaceutically acceptable salts thereof,

[0007] wherein Ar¹ is indole, benzimidazole, or benzotriazole,optionally substituted with lower alkyl (1-4C), halo, or lower alkoxy(1-4C);

[0008] X¹ is CO or an isostere thereof;

[0009] Y is optionally substituted alkyl, optionally substituted aryl,or optionally substituted arylalkyl;

[0010] n is 0 or 1;

[0011] Z is CH or N;

[0012] X² is CH, CH₂ or an isostere thereof; and

[0013] Ar² consists of one or two phenyl moieties directly coupled to X²and optionally substituted by halo, nitro, alkyl (1-6C), CN or CF₃, orby RCO, COOR, CONR₂, —NR₂, OR or SR, wherein R is H or alkyl(1-6C) orbyphenyl, itself optionally substituted by the foregoing substituents;

[0014] with the proviso that if Z is N, X¹ is CO, and Ar¹ is indole,then Ar¹ must be coupled to X¹ through the 2-, 5-, 6- or 7-position.

[0015] Thus, in one aspect, the invention is directed to compounds ofthe formula set forth above. In other aspects, the invention is directedto methods to produce these compounds, to pharmaceutical compositionscontaining them, and to methods of treating inflammation using thesecompounds. The invention is also directed to treating conditionsassociated with cardiac failure using the invention compounds and othercompounds described herein.

[0016] Modes of Carrying Out the Invention

[0017] The compounds of formula (1) set forth above are defined by thenature of the substituents on the piperazine or piperidine ring.

[0018] Ar¹ is an indole, benzimidazole, or benzotriazole nucleus whichmay be coupled to X¹ through any carbon in the ring nucleus. Preferably,however, coupling is through the 5- or 6-position, most preferablythrough the 5-position. The indole, benzimidazole or benzotriazolenucleus of Ar¹ may optionally be substituted with one or two alkylsubstituents at any remaining position, preferably at ring nitrogen.Preferred substituents are ethyl, isopropyl, methyl, isobutyl, andt-butyl.

[0019] X¹ is CO or an isostere thereof. Thus, in addition to CO, X¹ maybe CH₂, SO, SO₂, or CHOH. CO is preferred.

[0020] Z is CH or N.

[0021] X² is CH₂ if Ar² consists of a single phenyl moiety or CH if Ar²consists of two phenyl moieties or may be an isostere thereof. Thus, forappropriate embodiments of Ar², X² may consist of any of thealternatives set forth above for X¹.

[0022] The phenyl moieties represeiited by Ar² may optionally besubstituted by substituents including alkyl (1-6C), halo, RCO, COOR,CONR₂, OR, SR, NR₂, NO₂, CN, or CF₃, wherein R is H or alkyl (1-6C). Thephenyl moieties may also be substituted with an additional phenylresidue, preferably at the 4-position. The additional phenyl residue mayitself be substituted with the substituents set forth above. Theadditional phenyl may be substituted in all five positions, butpreferably less, preferably in 1-2 positions or not at all. Preferredsubstituents include halo and OCH₃. The substituents may occupy all fivepositions of the phenyl substituent, preferably 1-2 positions or thephenyl may be unsubstituted.

[0023] n may be 0 or 1, and is preferably 0. However, when n is 1, Y ispresent and may be alkyl, arylalkyl or aryl, all of which may optionallybe substituted by the substituents set forth above with regard to Ar².Preferred embodiments of Y include unsubstituted alkyl and unsubstitutedarylalkyl.

[0024] The compounds of formula (1) may be supplied in the form of theirpharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent on the compound of formula (1), the compound may also besupplied as a salt with a pharmaceutically acceptable cation.

[0025] Synthesis of the Invention Compounds

[0026] The compounds of the invention can be synthesized by firstcoupling the piperazine or piperidine residue to the indole,benzimidazole or benzotriazole moiety and then coupling with Ar² or bycoupling the already derivatized piperazine or piperidine to thenitrogen-containing bicyclic compound.

[0027] Thus, as shown in Reaction Scheme 1, a piperazine protected withtert-butyloxycarbonyl BOC) is coupled to 5-carboxybenzimidazole in areaction mixture containing a coupling agent such as EDAC in an inert,aprotic solvent to obtain the coupled carboxamide which is thendeprotected and treated with substituted or unsubstituted benzyl halidesor benzoyl halides.

[0028] Alternatively, as shown in Reaction Scheme 2, carboxylatedbenzimidazole (or indole or benzotriazole) is reacted with a piperazineor piperidine moiety already substituted by X²—Ar². In this reaction,the piperazyl or piperadyl derivative is directly reacted with thecarboxylated bicycloheteroatom-containing nucleus in the presence of acoupling agent such as EDAC in the presence of an inert solvent as setforth above.

[0029] In order to form the substituted piperazine required for Scheme2, piperazine is first converted to the BOC derivative and then reactedwith Ar²CHO in the presence of a borohydride under acidic conditions togive the substituted piperazine as shown in Reaction Scheme 3.

[0030] An alternative for coupling derivatized piperazine or piperidineto indole, benzimidazole or benzotriazole is shown in Reaction Scheme 4.In this reaction, the piperazine or piperidine ring is derivatized to asuitable leaving group as shown and then treated with a reducing agentsuch as NaH in an inert solvent to obtain the desired conjugate.

[0031] Another alternative is shown in Reaction Scheme 5. In thisapproach, a protected piperidone is reacted under reducing conditionswith the appropriate phosphonate ester to obtain a protected benzylenepiperidine. The product is then deprotected and reacted with thecarboxylate of indole, benzimidazole or benzotriazole using anappropriate, dehydrating agent. The product is then reduced to thedesired arylalkylated piperidine derivative.

[0032] Reaction Scheme 6 illustrates a method for preparing compounds ofthe invention in which the indole is substituted in the 6-membered ringthereof In Reaction Scheme 6, the appropriately substituted aniline isreacted with 1-methylmercaptyl-2,2-dialkoxyethane in the presence oftertiary butyryl chloride and base to provide the desired indole.Depending on the nature of the substitution of the aniline startingmaterial, more than one isomer may result as shown., The methylmercaptylgroup remaining on the 5-membered ring is reduced with Raney nickel anda mandatory methyl group included on the original aniline moiety isoxidized to the corresponding carboxylic acid. The resulting acid isthen reacted with the desired piperidine or piperazine derivative in thepresence of a coupling agent such as EDC.

[0033] Alkylation of the nitrogens on the indole, benzimidazole orbenzotriazole nucleus in the compounds per se is carried out byconventional means using the halide of the substituent to be added inthe presence of base and acetone.

[0034] R₁=for example 1,2,6-difluorophenyl; 3,4 difluorophenyl;2,3-difluorophenyl; 3,5difluorophenyl, 3-chlorophenyl;4-carbomethylphenyl; 4-methoxyphenyl; 4trifluoromethyloxyphenyl;4-methylphenyl; 6-chloropiperonyl, t-butylcarboxy; 3-trifluorophenyl.

[0035] R₂=for example 1,2,4-dichlorophenyl; 3,4-dichlorophenyl;cyclopentylethyl; trans (3-trifluoromethyl)cinnamoyl; 4-chlorophenyl;phenyl; 2-trifluorophenyl; propyl; methoxyphenyl; p-toluyl.

[0036] For synthesis of compounds wherein n is 1—i.e., wherein thepiperidine ring contains one additional substituent other than thosemandated in the compounds of the invention, the 4-substituted piperidineis first protected using BOC₂O in THF or other aprotic solvent and thenreacted with, for example, an alkyl iodide in the presence of S-butyllithium/TMEDA using, for example, ether as a solvent to produce thealkylated piperidine. The alkylated piperidine is then converted to theinvention compound by deprotection followed by formation of thecarboxamido linkage to the indoyl residue.

[0037] This is exemplified in Example 18 below.

[0038] Administration and Use

[0039] The compounds of the invention are useful in treating conditionsassociated with inflammation. Thus, the compounds of formula (1) ortheir pharmaceutically acceptable salts are used in the manufacture of amedicament for prophylactic or therapeutic treatment of mammals,including humans, in respect of conditions characterized by excessiveproduction of cytokines and/or inappropriate or unregulated cytokineactivity on such cells as cardiomyocytes, cardiofibroblasts andmacrophages.

[0040] The compounds of the invention inhibit the production ofcytokines such as TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of the inventionare shown herein to inhibit a member of the MAP kinase family variouslycalled p38 MPK (or p38), CSBP, or SAPK-2. The activation of this proteinhas been shown to accompany exacerbation of the diseases in response tostress caused, for example, by treatment with lipopolysaccharides orcytokines such as TNF and IL-1. Inhibition of p38 activity, therefore,is predictive of the ability of a medicament to provide a beneficialeffect in treating diseases such as coronary artery disease, congestiveheart failure, cardiomyopathy, myocarditis, vasculitis, restenosis, suchas occurs following coronary angioplasty, atherosclerosis, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions, multiple sclerosis, acute respiratorydistress syndrome (ARDS), asthma, chronic obstructive pulmonary disease(COPD), silicosis, pulmonary sarcosis, sepsis, septic shock, endotoxicshock, toxic shock syndrome, heart and brain failure (stroke) that arecharacterized by ischemia and reperfusion injury, surgical procedures,such as transplantation procedures and graft rejections, cardiopulmonarybypass, coronary artery bypass graft, CNS injuries, including open andclosed head trauma, inflammatory eye conditions such as conjunctivitisand uveitis, acute renal failure, glomerulonephritis, inflammatory boweldiseases, such as Crohn's disease or ulcerative colitis, graft vs hostdisease, bone resorption diseases like osteoporosis, type II diabetes,pyresis, psoriasis, cachexia, viral diseases such as those caused byHIV, CMV, and Herpes, and cerebral malaria.

[0041] Within the last several years, p38 has been shown to comprise agroup of MAP kinases designated p38α, p38β, p38γ and p38δ. Jiang, Y. etal. J Biol Chem (1996) 271:17920-17926 first reported characterizationof p38β as a 372-amino acid protein closely related to p38α. Kumar, S.et al. Biochem Biophys Res Comm (1997)235:533-538 and Stein, B. et al. JBiol Chem (1997) 272:19509-19517 reported a second isoform of p38β,p38β2, containing 364 amino acids with 73% identity to p38α. All ofthese reports show evidence that p38β is activated by proinflammatorycytokines and environmental stress, although the second reported p38βisoform, p38β2, appears to be preferentially expressed in the CNS, heartand skeletal muscle compared to the more ubiquitous tissue expression ofp38α. Furthermore, activated transcription factor-2 (ATF-2) was observedto be a better substrate for p38β2 than for p38α, thus suggesting thatseparate mechanisms of action may be associated with these forms. Thephysiological role of p38β1 has been called into question by the lattertwo reports since it cannot be found in human tissue and does notexhibit appreciable kinase activity with the substrates of p38α.

[0042] The identification of p38γ was reported by Li, Z. et al. BiochemBiophys Res Comm (1996) 228:334-340 and of p38δ by Wang, X., et al., JBiol Chem (1997) 272:23668-23674 and by Kumar, S., et al., BiochemBiophys Res Comm (1997)235:533-538. The data suggest that these two p38isoforms (γ and δ) represent a unique subset of the MAPK family based ontheir tissue expression patterns, substrate utilization, response todirect and indirect stimuli, and susceptibility to kinase inhibitors.

[0043] Various results with regard to response to drugs targeting thep38 family as between p38α and either the putative p38β1 or p38p2 orboth were reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A. et al. Chem and Biol (1995) 5:321-328. An additional paperby Wang, Y. et al. J Biol Chem (1998) 273:2161-2168 suggests thesignificce of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38β activity results in hypertrophy,whereas activation of p38α activity leads to myocyte apoptosis. Thus,selective inhibition of p38α activity as compared to p38β activity willbe of benefit in treating conditions associated with cardiac failure.These conditions include congestive heart failure, cardiomyopathy,myocarditis, vasculitis, vascular restenosis, valvular disease,conditions associated with cardiopulmonary bypass, coronary arterybypass, grafts and vascular grafts. Further, to the extent that theα-isoform is toxic in other muscle cell types, α-selective inhibitorswould be useful for conditions associated with cachexia attributed toTNF or other conditions such as cancer, infection, or autoimmunedisease.

[0044] Thus, the invention encompasses the use of compounds whichselectively inhibit the activity of the p38α isoform for treatingconditions associated with activation of p38α, in particular thoseassociated with cardiac hypertrophy, ischemia or other environmentalstress such as oxidation injury, hyperosmolarity or other agents orfactors that activate p38α kinase, or cardiac failure, for example,congestive heart failure, cardiomyopathy and myocarditis. Compoundsuseful in these conditions associated with heart failure are of theformula

[0045] or a pharmaceutically acceptable salt thereof

[0046] wherein Ar¹ is indole, benzimidazole, or benzotriazole,optionally substituted with lower alkyl (1-4C), halo, or alkoxy (1-4C);

[0047] X¹ is CO or an isostere thereof;

[0048] Y is optionally substituted alkyl, optionally substituted aryl,or optionally substituted arylalkyl;

[0049] n is 0 or 1;

[0050] Z is CH or N;

[0051] X² is CH, CH₂ or an isostere thereof; and

[0052] Ar² consists of one or two phenyl moieties directly coupled to X²and optionally substituted by halo, nitro, alkyl (1-6C), CN or CF₃, orby RCO, COOR, CONR₂, NR₂, OR or SR, wherein R is H or alkyl (1-6C) or byphenyl, itself optionally substituted by the foregoing substituents.

[0053] The manner of administration and formulation of the compoundsuseful in the invention and their related compounds will depend on thenature of the condition, the severity of the condition, the particularsubject to be treated, and the judgement of the practitioner;formulation will depend on mode of administration. As the compounds ofthe invention are small molecules, they are conveniently administered byoral administration by compounding them with suitable pharmaceuticalexcipients so as to provide tablets, capsules, syrups, and the like.Suitable formulations for oral administration may also include minorcomponents such as buffers, flavoring agents and the like. Typically,the amount of active ingredient in the formulations will be in the rangeof 5%-95% of the total formulation, but wide variation is permitteddepending on the carrier. Suitable carriers include sucrose, pectin,magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

[0054] The compounds useful in the invention may also be administeredthrough suppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

[0055] The compounds may also be administered topically, for topicalconditions such as psoriasis, or in formulation intended to penetratethe skin. These include lotions, creams, ointments and the like whichcan be formulated by known methods.

[0056] The compounds may also be administered by injection, includingintravenous, intramuscular, subcutaneous or intraperitoneal injection.Typical formulations for such use are liquid formulations in isotonicvehicles such as Hank's solution or Ringer's solution.

[0057] Alternative formulations include nasal sprays, liposomalformulations, slow-release formulations, and the like, as are known inthe art.

[0058] Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

[0059] The dosages of the compounds of the invention will depend on anumber of factors which will vary from patient to patient. However, itis believed that generally, the daily oral dosage will utilize 0.001-100mg/kg total body weight, preferably from 0.01-50 mg/kg and morepreferably about 0.01 mg/kg-10 mg/kg. The dose regimen will vary,however, depending on the conditions being treated and the judgment ofthe practitioner.

[0060] As implicated above, although the compounds of the invention maybe used in humans, they are also available for veterinary use intreating animal subjects.

[0061] The following examples are intended to illustrate but not tolimit the invention.

[0062] Examples 1-3 illustrate Reaction Scheme 1:

EXAMPLE 1 Preparation of 4-BOC piperazinyl-benzimidazole-5-carboxamide

[0063]

[0064] Benzimidazole-5-carboxylic acid (3.25 g, 20 mMol) was reactedwith 2.52 g (20 mMol) diisopropylcarbodiimide in dry DMF at roomtemperature for 15 minutes. To this reaction mixture was added 3.75 g(20 mMol) t-butyl-1-piperazine carboxylate, and the mixture was stirredfor 18 h. The mixture was poured into water and extracted with methylenechloride (3×100 mL). The combined extracts were washed again with water,brine and dried over MgSO₄. After removal of the solvent in vacuo, theresidue was chromatographed on a column of silica gel eluting withCHCl₃-Methanol (gradient, methanol 0 to 5%) to yield 5.69 g (86%) of theproduct. ¹H-NMR (DMSO d₆): s 8.3 (1H); m 7.7-7.6 (2H), m 7.2-7.3 (1H), m3.6-3.3 (8H) s 1.4 (9H); MS (ESI) m/e 330 (m⁺).

EXAMPLE 2 Preparation of piperazinyl-benzimidazole-5-carboxamide

[0065]

[0066] The N-BOC piperazinyl-benzimidazole-5-carboxamide (5.6 g) wasstirred in 20 mL 4 Molar HCl-dioxane for 1 h. The dioxane was removedunder reduced pressure to yield the hydrochloride salt in quantitativeyield. This was used for alkylations without any further purifications.

EXAMPLE 3 Preparation of4-(2,6difluorobenzyl)-piperazinyl-benzymidazole-5-carboxamide

[0067]

[0068] A. Piperazinyl-benzimidazole-5-carboxamide (0.186 g, 0.5 mMol)was taken in 5 mL DMF and 0.101 g (1 mMol) triethylamine was added andstirred for 15 minutes at room temperature. To this reaction mixture wasadded 0.104 g 2,6-difluorobenzyl bromide and the mixture was stirred for20 h. This was poured into water and extracted with methylene chloride(3×50 mL). The combined extract was further washed with brine, water anddried over MgSO₄. The solvent was removed in vacuo and the residuechromatographed on silica gel eluting with chloroform-methanol (0 to 5%methanol, gradient). Evaporation of the desired fraction gave 48.9 mg ofthe desired product; MS(ESI) m/e 356 (M⁺).

[0069] B. _Using the procedure set forth in paragraph A, the followingcompounds were prepared: By substituting for 2,6-difluorobenzylPreparation of bromide: 4-(2,3-difluorobenzyl)-piperazinyl-2,3-difluorobenzyl bromide benzimidazole-5-carboxamide MS (ESI) m/e 356(M⁺) 4-(3,5-difluorobenzyl)-piperazinyl- 3,5-difluorobenzylbromidebenzimidazole-5-carboxamide MS (ESI) m/e 356 (M⁺)4-(3-chlorobenzyl)-piperazinyl- 3-chlorobenzyl bromidebenzimidazole-5-carboxamide MS (ESI) m/e 354 (M⁺) 4-(4-carboxymethylbenzyl)-piperazinyl- methyl-4-(bromomethyl)- benzimidazole-5-carboxamidebenzoate MS (ESI) m/e 378 (M⁺) 4-(4-methoxybenzyl)-piperazinyl-4-methoxybenzyl chloride benzimidazole-5-carboxamide MS (ESI) m/e 350(M⁺) 4-(4-trifluoromethoxybenzyl)-piperazinyl- 4-(4-trifluoromethoxy)-benzimidazole-5-carboxamide benzyl bromide MS (ESI) m/e 404 (M⁺)4-(4-methylbenzyl)-piperazinyl- 4-methylbenzyl bromidebenzimidazole-5-carboxamide MS (ESI) m/e 334 (M⁺)4-(6-chloropiperonyl)-piperazinyl- 6-chloropiperonyl chloridebenzimidazole-5-carboxamide MS (ESI) m/e 399 (M⁺)4-(4-t-butylcarboxymethyl)-piperazinyl t-butyl bromoacetatebenzimidazole-5-carboxamide MS (ESI) m/e 344 (M⁺)4-(2,4-dichlorobenzoyl)-piperazinyl- 2,4-dichlorobenzoyl chloridebenzimidazole-5-carboxamide MS (ESI) m/e 403 (M⁺)4-(3,4-dichlorobenzoyl)-piperazinyl- 3,4-dichlorobenzoyl chloridebenzimidazole-5-carboxamide MS (ESI) m/e 403 (M⁺)4-(3-cyclopentylpropionyl)-piperazinyl- 3-cyclopentylpropionylbenzimidazole-5-carboxamide chloride MS (ESI) m/e 354 (M⁺)4-(cyclohexylcarbonyl)-piperazinyl- 3-cyclohexanecarbonylbenzimidazole-5-carboxamide chloride MS (ESI) m/e 340 (M⁺)4-[trans-3-(trifluoromethyl)-cinnamoyl]- trans-3-(trifluoromethyl)-piperazinyl-benzimidazole-5-carboxamide cinnamoyl chloride MS (ESI) m/e428 (M⁺) 4-(4-chlorobenzoyl)-piperazinyl- 4-chlorobenzoyl chloridebenzimidazole-5-carboxamide MS (ESI) m/e 369 (M⁺)4-benzoylpiperazine-benzimidazole-5- benzoyl chloride carboxamide MS(ESI) m/e 334 (M⁺) 4-(2-trifluoromethylbenzoyl-piperazinyl-2-(trifluoromethyl)- benzimidazole-5-carboxamide benzoyl chloride MS(ESI) m/e 402 (M⁺) 4-(4-methxybenzoyl)-piperazinyl- 4-methoxybenzoylchloride benzimidazole-5-carboxamide MS (ESI) m/e 364 (M⁺)

[0070] Example 4 illustrates Reaction Scheme 2:

EXAMPLE 4 Preparation of4-(3,4-dichlorophenyl)-piperazinyl-benzimidazole-5-carboxamide

[0071] A. Benzimidazole-5-carboxylic acid (1 mMol, 162 mg) was dissolvedin 5 mL dry DMF and reacted with1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride for 15minutes. 1-(3,4-dichlorophenyl)-piperazine, 1 mMol (231 mg) was addedfollowed by 10 mg DMAP. The mixture was stirred for 20 h at roomtemperature. The reaction mixture was poured into water and extractedwith methylene chloride (3×50 mL). The extracts were combined, washedwith brine, water and dried over MgSO₄. After evaporation of thesolvent, the residue was chromatographed on silica gel withchloroform-methanol (0-5% methanol, gradient). Evaporation of thedesired fractions gave 150 mg (40%) of the title compound; MS (ESI) m/e375 (M⁺).

[0072] B. Using the procedure of paragraph A, the following wereprepared: Substituting for 1-(3,4-dichlorophenyl) Preparation ofpiperazine, 4-(4-chlorobenzhydryl)-piperazinyl- 1-(4-chlorobenzhydryl)-benzimidazole-5-carboxamide piperazine MS (ESI) m/e 431 (M⁺)4-trans-1-cinnamyl piperazinyl- trans-1-cinnamyl piperazinebenzimidazole-5-carboxamide MS (ESI) m/e 346 (M⁺)4-(4-chlorophenyl)-piperazinyl- 1-(4-chlorophenyl)-piperazinebenzimidazole-5-carboxamide MS (ESI) m/e 341 (M⁺)4-[bis(4-fluorophenyl)-methy]-piperazinyl- 1-Bis(4-fluorophenyl)-benzimidazole-5-carboxamide methyl piperazine MS (ESI) m/e 432 (M⁺)4-(4-chlorobenzyl)-piperazinyl- 1-(4-chlorobenzyl)-piperazinebenzimidazole-5-carboxamide MS (ESI) m/e 354 (M⁺)4-(2-chlorobenzyl)-piperazinyl- 1-(2-chlorobenzyl)-piperazinebenzimidazole-5-carboxamide MS (ESI) m/e 354 (M⁺)4-benzylpiperazinyl-benzimidazole-5- 1-benzyl piperazine carboxamide MS(ESI) m/e 320 (M⁺)

[0073] Example 5 illustrates Reaction Scheme 3:

EXAMPLE 5 Preparation of4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide

[0074]

[0075] A. A mixture of 4-(methylthio)-benzaldehyde, 305 mg (2 mMol) andN-BOC piperazine, 372 mg (2 mMol) was stirred in dry methanol for 30minutes. To this mixture was added 1.6 g of polymer-supportedborohydride (2.5 mMol/g, on Amberlite, IRA-400, Aldrich) and the mixturewas stirred for 24 h. The polymer was removed by filtration andevaporation of the solvent yielded the4-BOC-1-(4-methylthio)-benzylpiperazine in quantitative yield. MS (ESI)m/e 322, (M⁺).

[0076] The 4-BOC-1-(4-methylthio)-benzylpiperazine was taken in 10 mL1:1 TFA/methylene chloride and stirred for 1 h at room temperature. Thesolvents were removed in vacuo and the residue was used withoutpurification for coupling with benznimidazole-5-carboxylic acid.

[0077] Benzimidazole-5-carboxylic acid (2 mMol, 324 mg) was taken in 15mL dry DMF and reacted with 2 mMol (382 mg) EDAC at room temperature for15 minutes. The above described 1-(4-methylthio)-benzylpiperazine wasadded as a DMF solution followed by 505 mg (5 mMol) TEA. The mixture wasstirred for 20 h. The mixture was poured into water and extracted withmethylene chloride (3×50 mL). The combined extracts were washed withbrine, water and dried over MgSO₄. The solvent was removed in vacuo andthe residue was chromatographed. Evaporation of the desired fractionsgave the title compound; MS (ESI) nve 366 (M⁺).

[0078] B. Using the procedure of paragraph A, the following wereprepared: Substituting for 4-(methylthio)- Preparation of benzaldehyde4-(3,4,5-trimethoxybenzyl)-piperazynyl- 3,4,5-methoxybenzaldehydebenzimidazole-5-carboxamide MS (ESI) m/e 410 (M⁺)4-(2-naphthylmethyl)-piperazynyl- 2-naphthaldehydebenzimidazole-5-carboxamide MS (ESI) m/e 370 (M⁺)4-(4-diethylaminobenzyl)-piperazinyl- 4-diethylaminobenzaldehydebenzimidazole-5-carboxamide MS (ESI) m/e 391 (M⁺)4-(biphenylmethyl)-piperazinyl- 4-biphenylcarboxaldehydebenzimidazole-5-carboxamide MS (ESI) m/e 396 (M⁺)4-(4-Phenoxybenzyl)-piperazinyl- 4-phenoxybenzaldehydebenzimidazole-5-carboxamide MS (ESI) m/e 412 (M⁺)4-(4-quinolinylmethyl)-piperazinyl- 4-quinolinecarboxaldehydebenzimidazole-5-carboxamide MS (ESI) m/e 371 (M⁺)

EXAMPLE 6 Preparation of4-(4-benzyl)-piperidinyl-benzimidazole-5-carboxamide

[0079]

[0080] Benzimidazole-5-carboxylic acid (1.62 g, 10 mMol) was reactedwith EDAC (1.92 g, 10 mMol) in 40 mL dry DMF at room temperature for 15minutes. To the reaction mixture was added 4-benzylpiperidine (1.75 g,10 mMol) and DMAP (20 mg, catalyst) and the mixture was stirred at roomtemperature for 20 h. It was poured into water and extracted withmethylene chloride (3×100 mL). The combined extract was washed withwater, brine and again with water. The extract was dried over MgSO₄ andevaporated. The residue was chromatographed on a column of silica gelwith chloroform-methanol (0 to 5% methanol). Evaporation of the desiredfractions gave 1 .5 g (47%) of the product after recrystallization fromethyl acetate-hexane. ¹HNMR (CDCl₃): δ=7.8 (s, 1H); 7.1-7.3 (m, 8H);4.8-4.7 (broad m, 1H), 3.7-3.9 (broad m, 1H); 3.1-2.7 (broad m, 2H);2.55 (d, 2H); 2.0-1.1 (m, 5H). MS (ESI) m/e 319 (M⁺), 318 (M⁺-H).

EXAMPLE 7 N-propylation of4-(4-benzyl)-piperidinyl-benzimidazole-5-carboxamide

[0081]

[0082] 4-(4-Benzyl)-piperidinyl-benzimidazole-5-carboxamide (318 mg, 1mMol) was taken in 20 mL acetone. KOH (solid, 280 mg, 5 mMol) was addedfollowed by 2-iodopropane (1 g˜6 mMol) and the mixture was refluxed for20 h. The acetone was removed in vacuo and the residue extracted fromwater with methylene chloride (3×50 mL). The extract was dried,evaporated and the residue chromatographed on silica gel withCHCL₃-Methanol (0 to 3% methanol). MS (ESI) m/e 360 (M⁺). HPLC: (VydacC18 column, 5 to 40% acetonitrile/water containing 0.1% TFA) two peaksshowing both isomers.

EXAMPLE 8 Preparation of 4-benzylpiperidinyl-indole-5-carboxamide.

[0083]

[0084] Indole-5-carboxylic acid (1.61 g, 10 mMol) was reacted with EDAC(1.92 g, 10 mMol) in 40 mL dry DMF for 15 minutes. 4-Benzylpiperidine(1.75 g, 10 mMol) was added followed by DMAP (20 mg, catalyst) and thereaction mixture was stirred for 20 h. The mixture was poured into waterand extracted with methylene chloride (3×100 mL)., The combined extractwas washed with dilute hydrochloric acid, saturated sodium bicarbonateand water and dried over MgSO₄. After evaporation of the solvent, theresidue was chromatographed with methylene chloride-methanol (0 to 2%methanol, gradient) to yield 1.60 g (50%) of the product afterrecrystailization from ether-Hexane. MS (ESI) m/e 318 (M⁺), (317⁺-H).¹HNMR (CDCl₃)δ=8.5 (s, 1H); 7.7 (s, 1H); 7.4-7.15 (m, 8H); 6.8 (s, 1H);4.8-4.6 (br, m, 1H); 4.1-3.9 9br, m, 1H); 3.1-2.7 (br, m, 2H); 2.6 (d,2H); 1.9-1.7 (br, m, 3H); 1.4-1,2 (br, m, 2H).

EXAMPLE 9 Preparation of4-benzylpiperidinyl-1-(2-propyl)-indole-5-carboxamide

[0085]

[0086] A mixture of 4-benzylpiperidinyl-benzimidazole-5-carboxamide (318mg, 1 mmol), solid KOH (280 mg, 5 nMmol) and 2iodopropane (1 g, 6 mmol)was refluxed in 20 mL acetone for 20 h. After the removal of acetone invacuo, the residue was extracted from water with methylene chloride(3×50 mL). The combined extract was dried, evaporated andchromatographed to yield 180 mg (50%) of the desired product.

[0087]¹HNMR (CDCl₃): δ=7.7 (s, 1H); 7.4-7.1 (m, 7H); 4.8-4.6 (m, 1H);3.0-2.7 (br, m, 4H); 2.6 (d, 2H); 1.8-1.45 (m, 3H); 1.5 (d, 6H); 1.3-1.1(m, 2H). MS (ESI) m/e 360 (M).

EXAMPLE 10 Preparation of4-(4-chlorobenzyl)-piperazinyl-1-(2-propyl)-indole-5-carboxamide

[0088]

[0089] 4-(4-Chlorobenzyl)piperazinyl-indole-5-carboxamide (420 mg, 1.32mMol) was taken in acetone. Solid KOH (280 mg, 5 mMol) was addedfollowed by the addition of 2-iodopropane (1 g, 6 mMol) and the mixturewas refluxed with stirring for 20 h. Acetone was removed in vacuo andthe residue was extracted from water using methylene chloride. Theextract was dried and evaporated and the residue was chromatographed ona column of silica gel using ethylacetate-hexane (ethylacetate 0 to 25%,gradient) and recrystallized from ether-hexane to yield 300 mg of theproduct. ¹HNMR (CDCl₃): δ=7.6 (s, 1H); 7.3-7.1 (m, 6H); 6.5 (s, 1H);4.65-4.55 (m, 1H); 3.8-3.5 (m, 4H); 3.4 (s, 2H); 2.4-2.5 (s, 4H); 1.5(d, 6H). MS (ESI) m/e 395 (M⁺).

EXAMPLE 11 Preparation of Additional Analogs

[0090] Additional analogs wherein the piperidinyl moiety is conjugatedto other positions of the indole nucleus were also prepared, as well astheir N-alkylated forms. In general, the procedures set forth in Example8 (for the conjugation) and Example 10 (for the alkylation) wereemployed. The compounds prepared are summarized below:

[0091] Using the procedure of Example 8, the positional analogs areprepared; as well as benzotriazole derivatives. Using the procedure setforth in Example 8, but substituting for Preparation ofindol-5-carboxylic acid 4-benzylpiperidinyl-indole-6-carboxamideIndole-6-carboxylic MS (ESI) m/e 318 (M⁺), (317⁺-H) acid4-benzylpiperidinyl-indole-3-carboxamide Indole-3-carboxylic MS (ESI)m/e 318 (M⁺), (317⁺-H) acid 4-benzylpiperidinyl-indoie-4-carboxamideIndole-4-carboxylic MS (ESI) m/e 318 (M⁺), (317⁺-H) acid4-benzylpiperidinyl-indole-7-carboxamide Indole-7-carboxylic MS (ESI)m/e 318 (M⁺), (317⁺-H) acid4-benzylpiperidinyl-benzotriazole-5-carboxamide Benzotriazole-5- MS(ESI) m/e 320 (M⁺), (319⁺-H) carboxylic acid Using the procedure ofExample 10, these compounds were alkylated, e.g., Using the procedureset forth in Example 11, but substituting for 4-chlorobenzyl piperidinylindole- Preparation of 5-carboxamide4-benzylpiperidinyl-1-(2-propyl)-indole-6- 4-benzyl piperidinyl-carboxamide MS (ESI) m/e 360 (M⁺) indole-6-carboxamide4-benzylpiperidinyl-1-(2-propyl)-indole- 4-benzyl piperidinyl-3-carboxamide MS (ESI) m/e 360 (M⁺) indole-3 carboxamide

EXAMPLE 12 Preparation of 4-benzylpiperidinyl-indole-1-carboxamide

[0092] A. Preparation of 4-benzylpiperidinyl-p-nitrophenyl carbamate

[0093] To a mixture of 4-benzylpiperidine (1.76 mL, 10 mMol) andtriethylamine (2.78 mL, 20 mMol) in 20 mL of dichloromethane cooled to0° C. was added a solution of 4-nitrophenyl chloroformate (2.22 g, 11mMol) in 10 mL dichloromethane. The mixture was stirred for 3 h at roomtemperature, poured into water and extracted with ethylacetate (3×50mL). The combined extracts were washed with 1M HCl, 1 M aqueous NaOH,water and brine. After drying over Na₂SO₄, evaporation of the solventgave the desired product as a tan solid. Yield 3.29 g,96.7%. ¹HNMR(CDCl₃) δ=8.27-8.2 (m, 2H); 7.35-7.13 (m, 7H); 4.25 (br, s, 2H);3.1-2.75 (m, 2H); 2.65-2.55 (m, 2H); 1.85-1.70 (m, 3H); 1.35-1.20 (m,2H). MS (ESI) m/e 340 (M⁺).

[0094] B. Reaction of Indole with 4-Benzylpiperidinyl-p-nitrophenylcarbamate

[0095] To a suspension of 60% NaH (0.08 g, 2 mMol) in 5 mL THF at RT wasadded a solution of indole (0.205 g, 1.75 mMol) in THF (5 mL). Afterstirring at RT for 30 minutes, a solution of the nitrophenyl carbamate(0.51 g, 1.5 mMol) in 5 mL THF was added. The mixture was stirred at RTfor 1 h, poured into water and extracted with ethyl acetate (3×50 mL).The combined extracts were washed with 1 M aq. NaOH, 1 M aq. HCl, waterand brine. After drying over Na₂SO₄, the solvent was evaporated and theresidue was purified by chromatography on silica gel usingacetone-hexane (5:95). Evaporation of the desired fractions gave 0.4 g(84%) of the desired product as a viscous oil. MS (ESI) m/e 318 (M⁺).

EXAMPLE 13 Preparation of 4-Benzylpiperidinyl-indole-2-carboxamide andits 1-isopropyl derivative

[0096]

[0097] To a solution containing 1.0 g (6.2 mMol) of indole-2-carboxylicacid and 1.1 g (6.2 mMol) of 4-benzylpiperidine in 20 mL of DCM wasadded 1.3 g (6.5 nMol) of EDC. The mixture was stirred at RT overnight.The solvent was evaporated and the residue was taken up in EtOAc andwashed with dil. HCl, 10% NaHCO₃ and brine. The organic layer was driedwith NaSO₄ and concentrated. On crystallization from 10% MeOH in EtOAcprovided 1.8 g (91%) of product as white solids, NMR (DMSO-d₆) δ=1.21(m, 4H), 1.63 (d, 2H), 1.85 (m, 1H), 2.58 (d, 2H), 2.82-3.12 (br, 2H),4.43 (d, 2H), 6.71 (s, 1H), 7.05 (t, 1H), 7.21 (m, 4H), 7 (m, 2H), 7.22(d, if), 7.64 (d, 11H), 11.55 (s, 1H). MS (ESI) m/e 318 (M⁺).

[0098] To a solution of 200 mg (0.63 mMol) of 4-benzylpid-indole-2-50carboxamide in 10 ml of acetone was added 321 mg (1.91Mol)of2-iodopropane and 106 mg (1.9 mMol) of powdered KOH. The mixture wasrefluxed for 3 h, then cooled, evaporated and the crude product waspurified by silica gel column chromatography using EtOAc: hexane (1:4)to provide the 4-Benzylpiperidinyl-1-(2-propyl)-indole-2-carboxamide aswhite solids, NMR (DMSO-d₆) δ=1.15 (m, 2H), 1.60 (d, 6H), 1.82 (m, 4H),2.56 (d, 2H), 2.72 (m, 1H), 3.02 (m, 1H), 4.15 (m, 1H), 4.80 (m, 1H),6.45 (s, 1H), 7.05-7.32 (m, 7H), 7.52 (d, 1H), 7.61 (d, 1H). MS (ESI)m/e 360 (M⁺).

EXAMPLE 14 Preparation of4-Chlorobenzylpiperazinyl)-indole-2-carboxamide

[0099]

[0100] A. A solution containing 1.0 g (6.2 mMol) of indole-2-carboxylicacid, 1.2 g (6.2 mMol) of BOC-piperazine, 1.2 g (6.2 mMol) EDC in 20 mLDCM was stirred overnight. The solvent was evaporated and the residuewas taken up in EtOAc and washed with dil. HCl, 10% NaHCO₃, and brine.The organics are dried with Na₂SO₄ and evaporated to get 1.92 g (94%) ofamide as white solids. The BOC group was deprotected by stirring with 4NHCl in dioxane solution for 1 h. The solids formed were filtered outwashed with ether and dried. To a solution of 300 mg (1.13 mMol) thissalt in 10 mL DMF was added 250 mg (1.2 mMol) 4-chlorobenzylbromide and165 mg (1.2 mMol) of K₂CO₃. The mixture was stirred at RT for 12 h, theproduct was extracted with ethyl acetate, washed with water and brine.On evaporation and trituration of the residue with EtOAc white solidsseparated which was collected by filtration. MS,(ESI) m/e 353 (M⁺).

[0101] B. Following the procedure of paragraph A, but substituting for4-chlorobenzylbromide, 3-chlorobenzyl bromide,3-chlorobenzylpiperazinyl)-indole-2-carboxamide was produced.

[0102] C. Following the procedure of paragraph A, but substituting, forindole-2-carboxylic acid, indole-5-carboxylic acid,4-chlorobenzylpiperazinyl)-indole-5-carboxamide was prepared.

EXAMPLE 15 Preparation of3-Chlorobenzylpiperazinyl-N-benzyl-benzimidazole-5- and 6-carboxamides

[0103] A. This paragraph describes the procedure for formation of theN-benzyl derivatives of the compounds of the invention; succeedingparagraphs describe alkylation with other moieties.

[0104] 3-Chlorobenzylpiperazinyl-benzimidazole-5-carboxamide (0.12 g,0.33 mMol) and the benzyl bromide (0.058 g, 0.33 mMol) in 15 mL DMF werecombined with K₂CO3 (0.09 g, 0.66 mMol). The mixture was stirred at RTovernight, then heated at 45° C. for 3 h. EtOAc was added and washedwith water. The organic layer was evaporated and the isomers wereseparated by silica gel column chromatography using 5% MeOH in EtOAc. ofisomer a (70 mg, 48%), MS (ESI) m/e 444 (M⁺) and of isomer b (40 mg,27%), MS (ESI) m/e 444 (M⁺) were obtained.

[0105] B. 3-Chlorobenzylpiperazinyl-N-(2-propyl)-benzimidazole-5- and6carboxamides.

[0106] 3-Chlorobenzylpiperazinyl-benzimidazole-5-carboxamide wasalkylated substituting 2-iodopropane for benzyl bromide in paragraph A.The isomers were separated using the same chromatographic conditions.Isomer a, MS (ESI) m/e 396 (M⁺).; isomer b, MS (ESI) m/e 396 (M⁺).

[0107] C. 3-Chlorobenzylpiperazinyl-N-methyl-benzimidazole-5- and6-carboxamide

[0108] 3-Chlorobenylpiperazinyl)-benzimidazole-5-carboxamide wasalkylated substituting iodomethane for benzyl bromide in the procedureof paragraph A. The isomers were separated using silica gel columnchromatography using 50% acetone in acetonitrile as the eluting solvent.Isomer a, MS (ESI) m/e 368 (M⁺), isomer b, MS (ESI) m/e 368 (M⁺).

[0109] Similarly, 4-benzylpiperidinyl-(1-methyl)-indole-5-carboxamide(MS (ESI) m/e 332 (M⁺)) was prepared from4-benzylpiperidinyl-indole-5-carboxamide.

[0110] D. 3-Chlorobenzylpiperazinyl-N-ethyl-benzimidazole-5- and6-carboxamides

[0111] 3-Chlorobenzylpiperazinyl-benzimidazole-5-carboxamide wasalkylated substituting iodoethane for benzyl bromide in paragraph A.Isomer a, MS (ESI) m/e 382 (M⁺); isomer b, MS (ESI) m/e 382 (M⁺).

[0112] Similarly, 4-benzylpiperidinyl-(1-ethyl)-indole-5-carboxamide (MS(ESI) m/e 346 (M⁺)) was prepared from4-benzylpiperidinyl-indole-5-carboxamide.

EXAMPLE 16 Preparation of4-(4-chlorobenzyl)-piperidinyl-indole-5-carboxamide

[0113]

[0114] This example illustrates Reaction Scheme 5.

[0115] a. Preparation of N-BOC-4-(4-chlorobenzylene)-piperidine

[0116] N-BOC-4-piperidone (2.0 g; 10 mmol) was taken withdiethyl-4-chlorobenzylphosphonate (2.6 g; 10 mmol) in dry THF. Sodiumhydride (400 mg, 60% dispersion in mineral oil; 10 mmol) was added andthe mixture was refluxed for three h. The THF was removed in vacuo andthe residue extracted from water with methylene chloride. The extractwas dried over MgSO₄, evaporated and the residue was chromatographed onsilica gel to yield 0.615 g of the desired product. ¹HNMR (CDCl₃): δ=7.3(d, 2H); 7.1 (d, 2H); 6.3 (s, 1H); 3.55-3.50 (m, 2H); 3.45-3.35 (m, 2H);2.45-2.35 (m, 2H); 2.30-2.25 (m, 2H); 1.25 (s, 9H). EIMS: 307 (M⁺), 251(M⁺-C₃H8).

[0117] b. Coupling of 4-Chlorobenzylene piperidine withindole-5-carboxylic Acid

[0118] The N-BOC-4-(4-chlorobenzylene-piperidine, described above, wasdeprotected by stirring in 20 mL 1:1 dichloromethane-trifluoroaceticacid for 1 h. It was evaporated and dried in vacuo for 1 h to remove alltraces of trifluoroacetic acid. It was redissolved in 15 mLdichloromethane and the TFA salt was neutralized by the addition of aslight excess of triethylamine. Solution A.

[0119] Indole-5-carboxylic acid 0.32 g (2 mmol) was reacted with 0.383 gEDAC in 30 mL dry dichloromethane for 15 minutes. To this solution wasadded the methylene chloride solution of 4-chlorobenzylene-piperidine(solution A) followed by the addition of 10 mg of DMAP. The mixture wasstirred for 20 h. The mixture was washed with water, 2N HCl, 5% sodiumcarbonate and then water. The organic solution was dried, evaporated andthe residue was chromatographed on silica gel eluting withethylacetate-hexane (1:4). Yield: 260 mg (37%). EIMS: 350 (M⁺), 315(M⁺-Cl) ¹HNMR (CDCl₃): δ=8.4 (s, 1H); 7.7 (s, 1H); 7.3-7.0 (m, 7H); 6.5(s, 1H); 6.25 (s, 1H); 3.8-3.0 (m, br, 4H); 2.6-2.20 (m, br, 4H).

[0120] C. Hydrogenation of4-(4-chlorobenzylene)-piperidine-indole-5-carboxamide

[0121] 4-(4-Chlorobenzylene)-piperidine-indole-5-carboxamide (240 mg,0.68 mmol) was dissolved in 40 mL THF. Pd/C (25 mg) was added and themixture was hydrogenated (1 atm) for 20 h with rapid stirring. Thecatalyst was removed by filtration through celite and the organicsolution was evaporated and the residue was recrystallized frommethylene chloride/hexane. Quantitative yield. EIMS: 352 (M⁺), 351(M⁺-H).

EXAMPLE 17

[0122] Using the general procedure set forth in Example 16, thefollowing are prepared: Substituting Preparation of for 4-chlorobenzylpiperidine 4-(3-chlorobenzyl)-piperidinyl-indole-5- 3-chlorobenzylpiperidine carboxamide MS (ESI) m/e 353 (M⁺)4-(2-chlorobenzyl)-piperidinyl-indole-5- 2-chlorobenzyl piperidinecarboxamide MS (ESI) m/e 353 (M⁺)

EXAMPLE 18 Synthesis ofcis-2-Methyl-4-phenylpiperidin-1-yl-indole-5-carboxamide

[0123]

[0124] (a) A mixture of 4-benzylpiperidine (3.52 mL, 20.0 mMol) anddi-tert-butyl-dicarbonate (5.45 g, 25.0 mMol) in 100 mL of THF wasrefluxed for 20 h. After cooling to rt the reaction mixture was pouredinto water and extracted with ethyl acetate (2×100 mL). the combinedorganic extract was washed with water and brine. The extract was driedover Na₂SO₄ arid, evaporated. The residue was chromatographed on acolumn of silica gel with 10% ethyl acetate-hexane. Evaporation of thedesired fractions gave 5.02 g (91%) of the product as an oil. MS (ESI)m/e 275 (M⁺).

[0125] (b) A mixture of 1-BOC-4-benzylpiperidine (0.825 g, 3.0 mMol) andN,N,N′,N′,-tetramethylethylenediamine (TMEDA) (0.59 mL, 3.9 mMol) in 6mL of Et₂O was cooled to −78° C. under argon. A 1.3M solution of s-BuLiin cyclohexane (3.0 mL, 3.9 mMol) was added dropwise. After the additionwas complete, the reaction mixture was stirred at −20° C. for 30 min andcooled back to −78° C. Methyl iodide (0.28 mL, 4.5 mmol) was added andthe reaction mixture was stirred at −78° C. for 5 min, the cooling bathremoved and stirring was continued an additional 3 min. The reactionmixture was poured into water and extracted with ethyl acetate (2×25mL). The combined organic extract was washed with water and brine. Theextract was dried over Na₂SO₄ and evaporated to give 0.58 g (67%) of anoil that was one spot by TLC (silica gel, 10% ethyl acetate-hexane).This material was used directly in the next step. MS (ESI) m/e 289 (M⁺).

[0126] (c) To a solution of 1-BOC-2-methyl-4-benzylpiperidine (0.29 g,1.0 mMol) in 5 mL of dichloromethane was added trifluoroacetic acid(TFA) (0.5 mL). After stirring at rt for 10 h the reaction mixture wasevaporated in vacuo and azeotroped twice with dichloromethane and twicewith hexane. The residue was dissolved in 5 mL of dichloromethane anddiisopropylethylamine (1.6 mL, 10 mMol) was added. In a separate flask amixture of 5-indolecarboxylic acid (0.19 g, 1.2 mMol) and EDAC (0.23 g,1.2 mMol) was dissolved in 15 mL of dichloromethane and stirred at rtfor 5 min. To this reaction mixture was added the first solution, andthe resulting mixture stirred at rt for 20 h. The reaction mixture waspoured into water and extracted with ethyl acetate (2×50 mL). Thecombined organic extract was washed with water and brine. The extractwas dried over Na₂SO₄ and evaporated. The residue was chromatographed ona column of silica gel with 1% MeOH-dichloromethane. Evaporation of thedesired fractions gave 0.18 g (54%) of the product as an oil.

[0127] When tested as described in Example 19 below, the title compoundhas an IC₅₀=280 nM.

EXAMPLE 19 Assay for p38 Kinase Inhibition

[0128] The compounds to be tested were solubilized in DMSO and dilutedinto water to the desired concentrations. The p38 kinase was diluted to10 μg/ml into a buffer containing 20 mM MOPS, pH 7.0,25 mM beta-glycerolphosphate, 2 mg/ml gelatin; 0.5 mM EGTA, and 4 mM DTT.

[0129] The reaction was carried out by mixing 20 μl test compound with10 μl of a substrate cocktail containing 500 μg/ml peptide substrate and0.2 mM ATP (+200 μCi/ml gamma-32P-ATP) in a 4× assay buffer. Thereaction was initiated by the addition of 10 μl of p38 kinase. Finalassay conditions were 25 mM MOPS, pH 7.0,26.25 mM beta-glycerolphosphate, 80 mM KCl, 22 mM MgCl₂, 3 mM MgSO₄, 1 mg/ml gelatin, 0.625 mMEGTA, 1 mM DTF, 125 μg/ml peptide substrate, 50 μM ATP, and 2.5 μg/mlenzyme. After a 40 minute incubation at room temperature, the reactionwas stopped by the addition of 10 μl per reaction of 0.25 M phosphoricacid.

[0130] A portion of the reaction was spotted onto a disk of P81phosphocellulose paper, the filters were dried for 2 minutes and thenwashed 4× in 75 mM H₃PO₄. The filters were rinsed briefly in 95%ethanol, dried, then placed in scintillation vials with liquidscintillation cocktail.

[0131] Alternatively, the substrate is previously biotinylated and theresulting reactions are spotted on SAM²™ streptavidin filter squares(Promega). The filters are washed 4× in 2M NaCl, 4× in 2M NaCl with 1%phosphoric acid, 2× in water, and briefly in 95% ethanol. The filtersquares are dried and placed in scintillation vials with liquidscintillation cocktail.

[0132] Counts incorporated are determined on a scintillation counter.Relative enzyme activity is calculated by subtracting background counts(counts measured in the absence of enzyme) from each result, andcomparing the resulting counts to those obtained in the absence ofinhibitor. IC₅₀ values were determined with curve-fitting plotsavailable with common software packages. Approximate IC₅₀ values werecalculated using formula

IC ₅₀ (app)=A×i/(1−A)

[0133] where A=fractional activity and i=total inhibitor concentration.

EXAMPLE 20 Comparison of Invention Compounds to Compounds in the PriorArt

[0134] As set forth above, WO98/06715 describes 3-carboxy indolepiperazine and 4-carboxy indole piperazine-containing compounds for useas antiinflammatory agents and inhibitors of p38 kinase-mediateddiseases. When tested in the above assay with regard to activity forp38α, it was shown that the compounds of the invention, containingpiperidinyl residues, were consistently more potent inhibitors of p38αthan the corresponding piperazines. These results are shown in Table 1as IC₅₀ in μM for inhibition of p38α.

[0135] All of the compounds in the table are 4-(4-benzyl piperidinyl)-or 4-(4-benzyl piperazinyl)-indole carboxamides. The point of attachmentof the carboxamide residue in the indole nucleus is shown in column 1 ofthe table. Thus, for example, the first pair of compounds in the table,represented by ring position 2, are 4-(4-benzylpiperidinyl)-indole-2-carboxamide and 4-(4-benzylpiperazinyl)-indole-2-carboxamide. TABLE 1 Ring Piperidinyl PiperazinylFold increase position IC₅₀ μM IC₅₀ μM Piperidinyl/Piperazinyl 22.66 >30 >11.3 3 0.163 4.74 29.1 4 0.159 1.54 9.7 5 0.150 1.71 11.4 60.462 5.52 11.9 7 7.04 >30 >4.3

[0136] The same compounds were tested for their specificity for p38α ascompared to results are shown in Table 2. TABLE 2 PiperidinylPiperazinyl Ring P38-β p38α IC₅₀ ratio P38-β p38-α IC₅₀ ratio positionIC₅₀ μM IC₅₀ μM β/α IC₅₀ μM IC₅₀ μM β/α 2 2.66 >30 3 1.77 0.163 10.934.0 4.74 7.17 4 2.43 0.159 15.3 24.0 1.54 15.6 5 3.02 0.150 20.1 25.81.71 15.1 6 3.83 0.462 8.27 39.1 5.52 7.08 7 7.04 >30

[0137] The compounds of the invention as well as those containingpiperazine, generally, are specific for p38α as compared to p38β. In thecase of coupling both to ring positions, 2 and 7, the IC₅₀ for the βform were not measured for both the piperazines and the piperdines. Itis seen that the specificity for α as opposed to β is generally of theorder of ten-fold.

[0138] The specificity of the compounds of the invention was also testedwith respect to other kinases, including p38-γ, ERK-2, PKA, PKC, cdc-2,EGF-R, and DNA-PK as shown in Table 3. The compounds indicated as 5, 3,4 and 6 are the same as those set forth in Tables 1 and 2—i.e., they arethe 4-(4-benzyl piperidinyl)-indole carboxamides with the numberindicating the ring position of the carboxamide. TABLE 3 IC₅₀ μM IC₅₀ μMIC₅₀ μM IC₅₀ μM KINASE 5 3 4 6 p38-α 0.150 0.163 0.159 0.462 p38-γ 228177 >300 >300 ERK-2 >300 >300 >300 >300 PKA 430 470 430 >500PKC >500 >500 >500 >500 cdc2 >500 >500 >500 >500EGF-R >500 >500 >500 >500 DNA-PK >500 >500 >500 450

[0139] The results are given in terms of approximate IC₅₀ (μM) valueswhen the compounds were tested at 50 μM except for p38α which is basedon IC₅₀ curves.

[0140] As shown, all of the compounds tested are highly specific forp38α as compared to these additional kinases.

1. A compound of the formula:

and the pharmaceutically acceptable salts thereof wherein Ar¹ is indole,benzimidazole, or benzotriazole, optionally substituted with lower alkyl(1-4C), halo, or lower alkoxy (1-4C); X¹ is CO or an isostere thereof; Yis optionally substituted alkyl, optionally substituted aryl, oroptionally substituted arylalkyl; n is 0 or 1; Z is CH or N; X² is CH,CH₂ or an isostere thereof; and Ar² consists of one or two phenylmoieties directly coupled to X² and optionally substituted by halo,nitro, alkyl (1-6C), CN or CF₃, or by RCO, COOR, CONR₂, NR₂, OR or SR,wherein R is H or alkyl (1-6C) or by phenyl, itself optionallysubstituted by the foregoing substituents; with the proviso that if Z isn, X¹ is CO, and Ar¹ is indole, Ar¹ must be coupled to X¹ through the2-, 5-, 6- or 7-position.
 2. The compound of claim 1 wherein n is
 0. 3.The compound of claim 1 wherein Z is CH.
 4. The compound of claim 3wherein X¹ is CO.
 5. The compound of claim 3 wherein Ar¹ is indole orbenzimidazole.
 6. The compound of claim 3 wherein n is
 0. 7. Thecompound of claim 3 wherein Ar¹ is coupled to X¹ through the 3, 4, 5 or6 position.
 8. The compound of claim 3 wherein X² is CH and Ar² consistsof two optionally substituted phenyl moieties.
 9. The compound of claim3 wherein X² is CH₂ or CO and Ar² consists of one optionally substitutedphenyl moiety.
 10. The compound of claim 3 wherein Ar² is phenyloptionally substituted with halo.
 11. The compound of claim 1 whereinAr¹ is coupled to X¹ through its 5-position.
 12. The compound of claim11 wherein X¹ is CO.
 13. The compound of claim 11 wherein n is
 0. 14.The compound of claim 11 wherein Ar¹ is optionally substituted indole orbenimidazole.
 15. The compound of claim 11 wherein Ar¹ is optionallysubstituted indole.
 16. The compound of claim 11 wherein X² is CH, or COand Ar² consists of one optionally substituted phenyl moiety.
 17. Thecompound of claim 11 wherein Ar² is phenyl optionally substituted withhalo.
 18. The compound of claim 1 wherein Ar¹ is optionally substitutedindole and Z is CH.
 19. The compound of claim 18 wherein Ar¹ isunsubstituted indole.
 20. The compound of claim 18 wherein X¹ is CO. 21.The compound of claim 18 wherein n is
 0. 22. The compound of claim 18wherein Ar¹ is coupled to X¹ through the 3, 4, 5 or 6 position.
 23. Thecompound of claim 18 wherein X¹ is CH and Ar² consists of two optionallysubstituted phenyl moieties.
 24. The compound of claim 18 wherein X² isCH₂ and Ar¹ consists of one optionally substituted phenyl moiety. 25.The compound of claim 18 wherein Ar² is phenyl optionally substitutedwith halo.
 26. The compound of claim 1 wherein Ar¹ is optionallysubstituted benzimidazole.
 27. The compound of claim 26 wherein X¹ isCO.
 28. The compound of claim 26 wherein n is
 0. 29. The compound ofclaim 26 wherein Ar¹ is coupled to X¹ through the 3, 4, 5 or 6 position.30. The compound of claim 26 wherein X² is CH and Ar² consists of twooptionally substituted phenyl moieties.
 31. The compound of claim 26wherein X² is CH₂ and Ar² consists of one optionally substituted phenylmoiety.
 32. The compound of claim 26 wherein Ar² is phenyl optionallysubstituted with halo.
 33. The compound of claim 1 which is4-benzylpiperidinyl-indole-5-carboxamide or is4-benzylpiperidinyl-benzimidazole-5-carboxamide.
 34. A method to treat acondition characterized by a proinflammation response which methodcomprises administering to a subject in need of such treatment acompound of the formula

or a pharmaceutically acceptable salt thereof wherein Ar¹ is indole,benzimidazole, or benzotriazole, optionally substituted with lower alkyl(1-4C), halo, or lower alkoxy (1-4C); X¹ is CO or an isostere thereof; Yis optionally substituted alkyl, optionally substituted aryl, oroptionally substituted arylalkyl; n is 0 or 1; Z is CH or N; X² is CH,CH₂ or an isostere thereof; and Ar² consists of one or two phenylmoieties directly coupled to X² and optionally substituted by halo,nitro, alkyl (1-6C), CN or CF₃, or by RCO, COOR, CONR₂, NR₂, OR or SR,wherein R is H or alkyl (1-6C) or by phenyl, itself optionallysubstituted by the foregoing substituents; with the proviso that if Z isN, X¹ is CO, and Ar¹ is indole, Ar¹ must be coupled to X¹ through the2-, 5-, 6- or 7-position.
 35. The method of claim 34 wherein saidcondition characterized by inflammation is acute respiratory distresssyndrome, asthma, chronic obstructive pulmonary disease, uveitis, IBD,acute renal failure, head trauma, or ischemic/reperfusion injury.
 36. Amethod to treat a heart condition associated with cardiac failure whichmethod comprises administering to a subject in need of such treatment acompound of the formula

or a pharmaceutically acceptable salt thereof wherein Ar¹ is indole,benzimidazole, or benzotriazole, optionally substituted with lower alkyl(1-4C), halo, or lower alkoxy (1-4C); X¹ is CO or an isostere thereof; Yis optionally substituted alkyl, optionally substituted aryl, oroptionally substituted arylalkyl; n is 0 or 1; Z is CH or N; X² is CH,CH₂ or an isostere thereof; and Ar² consists of one or two phenylmoieties directly coupled to X²and optionally substituted by halo,nitro, alkyl (1-6C), CN or CF₃, or by RCO, COOR, CONR₂, NR₂, OR or SR,wherein R is H or alkyl (1-6C) or by phenyl, itself optionallysubstituted by the foregoing substituents.
 37. The method of claim 36wherein said chronic heart condition is congestive heart failure,cardiomyopathy or myocarditis.
 38. A method to prepare a compound of theformula

or a pharmaceutically acceptable salt thereof wherein Ar¹ is indole,benzimidazole, or benzotriazole, optionally substituted with lower alkyl(1-4C), halo, or lower alkoxy (1-4C); X¹ is CO or an isostere thereof; Yis optionally substituted alkyl, optionally substituted aryl, oroptionally substituted arylalkyl; n is 0 or 1; Z is CH or N; X² is CH,CH₂ or an isostere thereof; and Ar² consists of one or two phenylmoieties directly coupled to X² and optionally substituted by halo,nitro, alkyl (1-6C), CN or CF₃, or by RCO, COOR, CONR₂, NR₂, OR or SR,wherein R is H or alkyl (1-6C) or by phenyl, itself optionallysubstituted by the foregoing substituents; which method comprises (a)reacting a compound of the formula Ar¹—COOH  (2) with a compound of theformula

 under conditions wherein the carboxamide is formed; or (b) reacting anoptionally substituted indole, benzimidazole or benzotriazole with acompound of the formula

wherein L is leaving group; or (c) reacting a compound of the formula

 with a compound of the formula Ar²—X²—M  (6) wherein M is a halide,under conditions of mild base.